The mammalian target of rapamycin (mTOR) plays a fundamental role in the regulation of skeletal muscle mass, however, the molecular mechanism(s) that regulate mTOR signaling have only been vaguely defined. Nevertheless, advances are being made, and recent studies suggest that the highly conserved translationally- controlled tumor protein (TCTP) can regulate mTOR signaling by acting as a guanine exchange factor (GEF) for the GTPase Rheb. Furthermore, previous studies have shown that the expression of TCTP can be rapidly induced by growth promoting stimuli through a mechanism that is sensitive to the mTOR inhibitor, rapamycin. Based on these observations, we have envisioned the potential for a mechanism in which TCTP regulates mTOR signaling in a feed-forward manner, and such a mechanism might explain how an acute growth stimulus (e.g. 60 high-resistance contractions) can promote a highly prolonged (>36hr) activation of mTOR signaling. In support of this possibility, we have found that TCTP expression is elevated in response to mechanical loading via an mTOR-dependent mechanism. Furthermore, we have determined that overexpression of TCTP is sufficient to induce hypertrophy. Combined, these observations have led us to our central hypothesis: growth promoting stimuli induce TCTP expression via an mTOR-dependent mechanism, and changes in TCTP expression, in-turn, regulate mTOR signaling, protein synthesis and fiber size. To test this hypothesis we will use a combination of in vivo biochemical, molecular and genetic approaches while pursuing the following three specific aims: 1) Determine if various growth promoting stimuli induce TCTP expression via an mTOR- dependent mechanism;2) Determine if the expression of TCTP regulates protein synthesis and fiber size;and 3) Determine if TCTP induces hypertrophy through an mTOR-dependent mechanism that requires TCTP's GEF activity towards Rheb. The results of these studies are expected to firmly establish TCTP as novel regulator of skeletal muscle mass and they will provide insight into how TCTP exerts this effect. Furthermore, if the central hypothesis is correct, the outcomes will expose a mechanism that substantially advances our understanding of how mTOR signaling and skeletal muscle mass are regulated.

Public Health Relevance

Skeletal muscle is crucial for movement and whole body metabolism, and consequently, the maintenance of skeletal muscle mass is essential for mobility, disease prevention and quality of life. Hence, this project is relevant to public health because the outcomes could lead to the identification of targets for therapies that are aimed at preventing skeletal muscle atrophy during conditions such as aging, immobilization, bedrest, spaceflight, cachexia, muscular dystrophies and myopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR063256-01A1
Application #
8443132
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2012-09-10
Project End
2014-08-31
Budget Start
2012-09-10
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$203,175
Indirect Cost
$68,175
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Goodman, Craig A; Coenen, Allison M; Frey, John W et al. (2017) Insights into the role and regulation of TCTP in skeletal muscle. Oncotarget 8:18754-18772
Goodman, Craig A; Hornberger, Troy A; Robling, Alexander G (2015) Bone and skeletal muscle: Key players in mechanotransduction and potential overlapping mechanisms. Bone 80:24-36
Goodman, Craig A; Dietz, Jason M; Jacobs, Brittany L et al. (2015) Yes-Associated Protein is up-regulated by mechanical overload and is sufficient to induce skeletal muscle hypertrophy. FEBS Lett 589:1491-7
Goodman, Craig A; Hornberger, Troy A (2014) New roles for Smad signaling and phosphatidic acid in the regulation of skeletal muscle mass. F1000Prime Rep 6:20
Goodman, Craig A (2014) The role of mTORC1 in regulating protein synthesis and skeletal muscle mass in response to various mechanical stimuli. Rev Physiol Biochem Pharmacol 166:43-95
Goodman, Craig A; McNally, Rachel M; Hoffmann, F Michael et al. (2013) Smad3 induces atrogin-1, inhibits mTOR and protein synthesis, and promotes muscle atrophy in vivo. Mol Endocrinol 27:1946-57